tbuckley/cabot-search huggingface dataset:
H3K4me3 remodeling induced acquired resistance through O-GlcNAc transferase
Authors: Dinoop Ravindran Menon, Heinz Hammerlindl, Gregory Gimenez, Sabrina Hammerlindl, Elmar Zuegner, Joachim Torrano, Natalie Bordag, Abdullah Al Emran, Maybelline Giam, Simon Denil, Norman Pavelka, Aik-Choon Tan, Richard A. Sturm, Nikolas K. Haass, Giulia Rancati, Meenhard Herlyn, Christoph Magnes, Michael R. Eccles, Mayumi Fujita, Helmut Schaider
Journal: Drug Resistance Updates (2023)

Drivers of the drug tolerant proliferative persister (DTPP) state have not been well investigated. Histone H3 lysine-4 trimethylation (H3K4me3), an active histone mark, might enable slow cycling drug tolerant persisters (DTP) to regain proliferative capacity. This study aimed to determine H3K4me3 transcriptionally active sites identifying a key regulator of DTPPs.Deploying a model of adaptive cancer drug tolerance, H3K4me3 ChIP-Seq data of DTPPs guided identification of top transcription factor binding motifs. These suggested involvement of O-linked N-acetylglucosamine transferase (OGT), which was confirmed by metabolomics analysis and biochemical assays. OGT impact on DTPPs and adaptive resistance was explored in vitro and in vivo.H3K4me3 remodeling was widespread in CPG island regions and DNA binding motifs associated with O-GlcNAc marked chromatin. Accordingly, we observed an upregulation of OGT, O-GlcNAc and its binding partner TET1 in chronically treated cancer cells. Inhibition of OGT led to loss of H3K4me3 and downregulation of genes contributing to drug resistance. Genetic ablation of OGT prevented acquired drug resistance in in vivo models. Upstream of OGT, we identified AMPK as an actionable target. AMPK activation by acetyl salicylic acid downregulated OGT with similar effects on delaying acquired resistance.Our findings uncover a fundamental mechanism of adaptive drug resistance that governs cancer cell reprogramming towards acquired drug resistance, a process that can be exploited to improve response duration and patient outcomes.
P1191: A NOVEL PROGNOSTIC MODEL OF DLBCL PATIENTS BASED ON CUPROPTOSIS RELATED GENES
Authors: LI Fu, LI Jiali, Jun Rao, Shijia Lin, Song Dong, Xixi Xiang, LI Gao, XI Zhang
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: The current classification system for diffuse large B-cell lymphoma (DLBCL) cannot fully explain the prognostic differences of DLBCL patients. Cuproptosis is a newly discovered programmed cell death which depend on copper ions. However, the potential role of cuproptosis in the prognosis of DLBCL patients remains unclear. Aims: In this study, a prognostic model based on cuproptosis-related genes was constructed using public database. The target compounds that may act on copper death related genes were also searched. Methods: COX regression analysis was performed on training set-GSE31312 to construct a prognostic model based on copper death-related genes, and validation set-GSE181063 was used to verify the prognostic model. GSEA was used to explore the underlying mechanism of the difference in prognosis of DLBCL patients. Finally, molecular docking was used to screen for compounds that may act on cuproptosis-related genes. Results: Uni-COX regression analysis was performed on cuproptosis-related genes of GSE31312, and 6 key cuproptosis-related genes that significantly affected the prognosis of patients were screened out. Multi-COX regression analysis was performed on these 6 cuproptosis-related genes. A prognostic model based on 5 cuproptosis-related genes was constructed (CDKN2A × 1.547905713 - DLAT × 2.241073725 - DLD × 1.907442964 - LIPT1 × 2.689158994 - MTF1 × 2.069682266). According to this model, DLBCL patients were divided into high-risk and low-risk groups. The survival time of high-risk patients was significantly shorter than that of the low-risk group (P = 2.636 × 10-7). In the validation set GSE181063, the survival time of the high-risk group was also shorter than low-risk group (P = 2.251 × 10-4). Among the 5 cuproptosis-related genes, only CDKN2A played a tumorigenesis effect. Finally, three small molecules with the lowest binding energy of CDKN2A were found by virtual docking: Irinotecan, Lumacaftor and Nilotinib, which may be used as potential targeted drugs. Conclusion: A prognostic model based on 5 cuproptosis-related genes was constructed, and 3 potential targeted inhibitors of CDKN2A were screened out by molecular docking. Keywords: DLBCL, Prognostic factor
P765: MIB2/SUZ12 REGULATED THE PROLIFERATION OF PNH CLONE
Authors: Lijie Zeng, Hui Liu, Chaomeng Wang, Liyan LI, Zonghong Shao, Rong Fu
Journal: HemaSphere (2023)

Topic: 11. Bone marrow failure syndromes incl. PNH - Biology & Translational Research Background: On the basis of our previous studies, we found that SUZ12 participate in the proliferation of PNH clone by regulating H3K27me3. And then we used immunoprecipitation and mass spectrometry to identify that MIB2 interacting with SUZ12. Aims: We explore the mechanism of MIB2 regulating the proliferation of PNH clones. We hope to improve the pathogenesis of PNH and explore a new target. Methods: We have constructed a PIGA gene knock-out K562 cell line(K562-KO) by CRISPR/cas9. Immunoprecipitation and mass spectrometry were used to identify SUZ12 interacting proteins. And then, COIP was used to verify their interaction. Next, immunofluorescence was used to explore subcellular localization of SUZ12 and MIB2 protein. Furthermore, RNA-seq was used to explore signaling pathway. Finally, colony formation assays was used to clarify proliferative abilities of cells and western blot was used to test protein level changes and FCS was used to test apoptosis level of cells. Results: We found that MIB2 protein exists in cell membrane, cytoplasm and nucleus, MIB2 and SUZ12 are co-located in nucleus. GSEA analysis of the RNA-seq results in the control and siMIB2 groups showed that PRC2-related target genes were up-regulated in siMIB2 group. What’s more, we observed that SUZ12 and H3K27me3 expression level, cell proliferation ability was significantly decreased after MIB2 knockdown, while cell apoptosis level was significantly increased when knockdown MIB2. But in the SUZ12 plasmid rescue group after MIB2 knockdown, we found that SUZ12 protein level, H3K27me3 level, cell proliferation ability and the level of apoptosis were significantly restored. Summary/Conclusion: We found that MIB2 and SUZ12 were co-located in cell nucleus, MIB2 intervened SUZ12 protein level and the function of PRC2 complex, which regulating the proliferation of PNH clone. Our results showed the mechanism of MIB2 in PNH clone proliferation and might provide a new target for PNH.Keywords: Paroxysmal nocturnal hemoglobinuria (PNH), Clonal expansion, Proliferation
Incorporating digitally derived endpoints within clinical development programs by leveraging prior work
Authors: Amy Bertha, Rinol Alaj, Imein Bousnina, Megan K. Doyle, Danielle Friend, Rasika Kalamegham, Lauren Oliva, Igor Knezevic, Frank Kramer, Hans-Peter Podhaisky, Sven Reimann
Journal: npj Digital Medicine (2023)

Digital health technologies (DHTs) enable remote data collection, support a patient-centric approach to drug development, and provide real-time data in real-world settings. With increasing use of DHTs in clinical care and development, we expect a growing body of evidence supporting use of DHTs to capture endpoint data in clinical trials. As the body of evidence grows, it will be critical to ensure that available prior work can be leveraged. We propose a framework to reuse analytical and clinical validation, as well as verification data, generated for existing DHTs. We apply real life case studies to illustrate our proposal aimed at leveraging prior work, while applying the V3 framework (verification, analytical validation, clinical validation) and avoiding duplication. Utilizing our framework will enable stakeholders to share best practices and consistent approaches to employing these tools in clinical studies, build on each other's work, and ultimately accelerate evidence generation demonstrating the reproducibility and value add of these new tools.
PB2468: A RETROSPECTIVE STUDY OF ELTROMBOPAG IN PATIENTS WITH THROMBOCYTOPENIA AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: Liangming MA, Dan Wang, Keru Shi
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Persistent thrombocytopenia is a common complication after allogenic (allo-SCT).Eltrombopag is the currently available thrombopoietin receptor agonists(TPO-Ras),The study evaluated the safey and efficacy of eltrombopag in 34cases Aims: To observe the effect of eltrombopag on patients with thrombocytopenia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: The clinical data of 60 patients with thrombocytopenia after allogeneic hematopoietic stem cell transplantation in the Department of Hematology, Shanxi Bethune Hospital from March 2018 to March 2022 were retrospectively analyzed. Sixty patients were divided into eltrobopag group(n=34)and control group (n=26),the time nodes of platelets reaching 20×109/L and 50×109/L and the median transfusion times of platelets reaching 50×109/L were compared between the two groups; The time nodes of platelet reaching OR and CR and OR rate and CR rate in the two groups. The treatment protocol was approved by the Ethical Committee of Shanxi Bethune Hospital and informed consent was obtained from the patient. Results: Receive eltrobopag time:treatment group after transplantation 50d(31-123d);The median time of platelet reach 20×109/L in the treatment group and the control group were 6days(1-16daya),13days (5-28days) (statistical difference between the two P<0.05),The median time of platelet reach 50×109/L in the treatment group and the control group were 21days(5-55days),27days（15-60days) (statistical difference between the two P<0.05),The recovery time of platelet in the treatment group was 7 and 6 days earlier than that in the control group.The median transfusion times of irradiated platelet in the control group were 5times(1-12times）and 7times（3-14times）,two more times in the control group than in the treatment group;The median time for platelet to reach OR and CR in the treatment group and the control group were 14days（1-36days）、22days（11-43days）and 29days（14-65days）、35days（27-55days）.The recovery time of platelet in the treatment group was 8 and 6 days earlier than that in the control group.The difference between the two groups was statistically significant (P<0.05).OR rate and CR rate in the treatment group and the control group were 97.1%,76.9% and 85.3%,61.5%.After follow-up to September 2022, the disease-free survival rates of the two groups were 91.2% and 88.5%. Summary/Conclusion: Eltrombopag can promote the recovery of thrombocytopenia after allogeneic hematopoietic stem cell transplantation,and the patient’s tolerance is good,which is worthy of further clinical application. Keywords: Thrombocytopenia, Treatment, Allogeneic hematopoietic stem cell transplant
P1587: PREVALENCE OF RED BLOOD CELL ABNORMALITIES AMONG DONATED BLOOD IN FAYOUM UNIVERSITY HOSPITAL, EGYPT
Authors: Salwa Bakr, Eman Yousef, Eman Ezzat, Asmaa Younis Elsary, Azza Alamir, Mona Gamal
Journal: HemaSphere (2023)

Topic: 31. Transfusion medicine Background: Effectiveness of red blood cells transfusion in a given unit that relied on both quantity and quality of donated cells undoubtedly affects prognostic outcomes. Because assessing such parameters during donation is routine except for the functional hemoglobin abnormalities that insure the quality of red cells delivered and their life span. Aims: To determine the frequency of subclinical iron deficiency, thalassemia trait, sickle trait, and G6PD enzymopathies among donated blood in Fayoum University Hospital, Egypt. Methods: This cross sectional study conducted on 200 volunteer blood donors who met the national standard criterion of blood donation. Complete blood count with reticulocyte parameters, serum ferritin, sickling test, G6PD assay, Mentzer index (MI), and naked-eye single tube red cell osmotic fragility test (NESTROFT) were performed. Results: Functional hemoglobin abnormalities represented about 29% of our study donated blood. Out of them, 4.5% had frank subclinical iron deficiency, 6.5% had borderline iron deficiency, 11% had positive sickling test, 19% had G6PD deficiency, and 9.5% had suspicious thalassemia trait with MI and NESTROFT. Leucopenia was observed in 12% of all donors. Summary/Conclusion: Screening for subclinical functional hemoglobin abnormalities seems to be mandatory before issuing donated blood unit particularly for critical cases such as neonate, patients on chronic blood transfusion therapy, and advanced end stage organ failure. Keywords: Blood transfusion, Iron deficiency, Hemoglobinopathy, G6PD
Multifaceted role of redox pattern in the tumor immune microenvironment regarding autophagy and apoptosis
Authors: Yuqing Ren, Ruizhi Wang, Siyuan Weng, Hui Xu, Yuyuan Zhang, Shuang Chen, Shutong Liu, Yuhao Ba, Zhaokai Zhou, Peng Luo, Quan Cheng, Qin Dang, Zaoqu Liu, Xinwei Han
Journal: Molecular Cancer (2023)

Abstract The reversible oxidation-reduction homeostasis mechanism functions as a specific signal transduction system, eliciting related physiological responses. Disruptions to redox homeostasis can have negative consequences, including the potential for cancer development and progression, which are closely linked to a series of redox processes, such as adjustment of reactive oxygen species (ROS) levels and species, changes in antioxidant capacity, and differential effects of ROS on downstream cell fate and immune capacity. The tumor microenvironment (TME) exhibits a complex interplay between immunity and regulatory cell death, especially autophagy and apoptosis, which is crucially regulated by ROS. The present study aims to investigate the mechanism by which multi-source ROS affects apoptosis, autophagy, and the anti-tumor immune response in the TME and the mutual crosstalk between these three processes. Given the intricate role of ROS in controlling cell fate and immunity, we will further examine the relationship between traditional cancer therapy and ROS. It is worth noting that we will discuss some potential ROS-related treatment options for further future studies.
Long COVID and Significant Activity Limitation Among Adults, by Age — United States, June 1–13, 2022, to June 7–19, 2023
Authors: Nicole D. Ford, Douglas Slaughter, Deja Edwards, Alexandra Dalton, Cria Perrine, Anjel Vahratian, Sharon Saydah
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Long COVID is a condition encompassing a wide range of health problems that emerge, persist, or return following COVID-19. CDC analyzed national repeat cross-sectional Household Pulse Survey data to estimate the prevalence of long COVID and significant related activity limitation among U.S. adults aged ≥18 years by age group. Data from surveys completed between June 1-13, 2022, and June 7-19, 2023, indicated that long COVID prevalence decreased from 7.5% (95% CI = 7.1-7.9) to 6.0% (95% CI = 5.7-6.3) among the overall U.S. adult population, irrespective of history of previous COVID-19, and from 18.9% (95% CI = 17.9-19.8) to 11.0% (95% CI = 10.4-11.6) among U.S. adults reporting previous COVID-19. Among both groups, prevalence decreased from June 1-13, 2022, through January 4-16, 2023, before stabilizing. When stratified by age, only adults aged <60 years experienced significant rates of decline (p<0.01). Among adults reporting previous COVID-19, prevalence decreased among those aged 30-79 years through fall or winter and then stabilized. During June 7-19, 2023, 26.4% (95% CI = 24.0-28.9) of adults with long COVID reported significant activity limitation, the prevalence of which did not change over time. These findings help guide the ongoing COVID-19 prevention efforts and planning for long COVID symptom management and future health care service needs.
Clinical Evidence for Association of Electroacupuncture with Improved Colorectal Postoperative Gastrointestinal Function Recovery: A Systematic Review and Meta-Analysis
Authors: Lu-yi Wu, Bing-Li Chen, Hong-Xiao Xu, Hui-Rong Liu, Jia Zhou, Jing Li, Li-Ming Chen, Lu Zhu, Lu-yi Wu, Mu-En Gu, Qin Qi, Rui Zhong, Shi-Fen Xu, Yan Huang, Zhao-Qing Wang
Journal: International Journal of Surgery (2023)

Background: Studies on the efﬁcacy of electroacupuncture (EA) on postoperative gastrointestinal function (PGIF) recovery in colorectal cancer (CRC) patients have been increasing, but the findings are inconsistent. To evaluate the effectiveness and safety of EA on PGIF recovery in patients with CRC based on existing randomized controlled trials (RCTs) and assess whether the current evidence is conclusive by trial sequential analysis (TSA). Materials and Methods: PubMed, Embase (Ovid), Medline, Cochrane Library, Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang) were searched for RCTs published from inception to November 6, 2022. RCTs in which EA was compared with sham control (sham electroacupuncture, SA) or usual care (UC) for managing PGIF recovery in patients with CRC were included. Following the preferred reporting items for systematic reviews and meta-analyses, two reviewers independently extracted data as well as assessed the risk of bias using the cochrane risk of bias tool (ROB 2.0) and the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Data were screened and extracted independently using predesigned forms. Data were pooled using a random-effects model. Results: Sixteen studies, including 1290 patients with CRC that showed PGIF recovery met the inclusion criteria. The meta-analysis revealed that compared with the UC group, EA + UC group showed a significant improvement in the time to first flatus (MD: -14.59, 95% CI: -22.75 to -6.43, P &lt; 0.01), time to first defecation (MD: -20.28, 95% CI: -28.14 to -12.42, P &lt; 0.01), and time to first bowel sounds (MD: -11.79, 95% CI: -18.97 to -4.60, P &lt; 0.01). The TSA confirmed the better treatment outcomes of EA compared with UC. Compared with the SA group, EA + UC group showed a significant improvement in the time to first flatus (MD: -10.48, 95% CI: [-13.74, -7.21], P &lt; 0.01) and time to first defecation (MD: -10.72, 95% CI: [-20.14, -1.30], P = 0.03), and the improvement in time to first bowel sounds (MD: -5.41, 95% CI -12.43 to 1.60, P = 0.13) was similar. The TSA indicated there might be false positive results and further studies with a larger overall sample size are deemed necessary. The reported adverse events related to acupuncture were less serious. Conclusion: EA has great potential to accelerate the recovery of PGIF for patients with CRC. RCTs with usual care control was sufficient. Additional pre-registered and sham-controlled RCTs are still needed to validate the safety and efficacy of EA.
An Outbreak of <i>Salmonella</i> Typhimurium Infections Linked to Ready-To-Eat Tofu in Multiple Health Districts — Ontario, Canada, May–July 2021
Authors: Victoria Osasah, Yvonne Whitfield, Janica Adams, Affan Danish, Richard Mather, Mehdi Aloosh
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

From May to mid-August 2021, the Ontario, Canada provincial public health agency, Public Health Ontario, in collaboration with local public health authorities and federal food safety partners, investigated a spatiotemporal cluster of 38 patients with Salmonella Typhimurium infections across multiple public health districts in Ontario. Five (13%) patients were hospitalized; no deaths were reported. The outbreak was linked to consumption of ready-to-eat seasoned tofu from one manufacturer that was distributed to multiple Ontario restaurants. Isolates from the seasoned tofu were within one or fewer allele differences to the outbreak strain by whole genome sequencing. Evidence from food safety investigations conducted by local public health authorities and the Canadian Food Inspection Agency (CFIA) revealed that unsanitary conditions could have led to cross-contamination of the tofu, and insufficient heating of the tofu at the production level likely resulted in failure to eliminate the pathogen. The CFIA issued a food recall for the tofu at hotel, restaurant, and institution levels. Tofu was identified as a novel outbreak-associated food vehicle for S. Typhimurium in this outbreak. Interventions that target the production level and all parts of the supply chain and include additional safeguarding steps that minimize microbial growth are important.
CCR2 macrophage response determines the functional outcome following cardiomyocyte transplantation
Authors: Praveen Vasudevan, Markus Wolfien, Heiko Lemcke, Cajetan Immanuel Lang, Anna Skorska, Ralf Gaebel, Anne-Marie Galow, Dirk Koczan, Tobias Lindner, Wendy Bergmann, Brigitte Mueller-Hilke, Brigitte Vollmar, Bernd Joachim Krause, Olaf Wolkenhauer, Gustav Steinhoff, Robert David
Journal: Genome Medicine (2023)

The immune response is a crucial factor for mediating the benefit of cardiac cell therapies. Our previous research showed that cardiomyocyte transplantation alters the cardiac immune response and, when combined with short-term pharmacological CCR2 inhibition, resulted in diminished functional benefit. However, the specific role of innate immune cells, especially CCR2 macrophages on the outcome of cardiomyocyte transplantation, is unclear. We compared the cellular, molecular, and functional outcome following cardiomyocyte transplantation in wildtype and T cell- and B cell-deficient Rag2del mice. The cardiac inflammatory response was assessed using flow cytometry. Gene expression profile was assessed using single-cell and bulk RNA sequencing. Cardiac function and morphology were determined using magnetic resonance tomography and immunohistochemistry respectively. Compared to wildtype mice, Rag2del mice show an increased innate immune response at steady state and disparate macrophage response after MI. Subsequent single-cell analyses after MI showed differences in macrophage development and a lower prevalence of CCR2 expressing macrophages. Cardiomyocyte transplantation increased NK cells and monocytes, while reducing CCR2-MHC-IIlo macrophages. Consequently, it led to increased mRNA levels of genes involved in extracellular remodelling, poor graft survival, and no functional improvement. Using machine learning-based feature selection, Mfge8 and Ccl7 were identified as the primary targets underlying these effects in the heart. Our results demonstrate that the improved functional outcome following cardiomyocyte transplantation is dependent on a specific CCR2 macrophage response. This work highlights the need to study the role of the immune response for cardiomyocyte cell therapy for successful clinical translation.